OBJECTIVE: Treatment of excessive sleepiness in the context of obstructive sleep apnea (OSA) may be particularly difficult in those with depression because depression and/or antidepressant medications may cause sleepiness and fatigue in addition to that due to the OSA. This study evaluating armodafinil, a nonamphetamine wakefulness-promoting medication, is the first trial for treatment of excessive sleepiness in patients with treated OSA and comorbid depression. METHOD: Men and women with OSA diagnosed using International Classification of Sleep Disorders criteria being treated with continuous positive airway pressure and comorbid major depressive disorder or dysthymic disorder according to DSM-IV-TR criteria were enrolled into a 12-week, randomized, double-blind, parallel-group study between September 2007 and March 2009 at 60 outpatient sites. Patients maintained on stable monotherapy with a serotonergic antidepressant and with a 17-item Hamilton Depression Rating Scale score < 17 received placebo or armodafinil (target dose: 200 mg once daily). Coprimary outcomes were the proportion of patients with at least minimal improvement on the Clinical Global Impression of Change (CGI-C) as related to excessive sleepiness and mean change from baseline in Maintenance of Wakefulness Test mean sleep latency at final visit; the key secondary outcome was mean change in the Epworth Sleepiness Scale score. RESULTS: 249 patients were enrolled: 125 in the armodafinil group and 124 in the placebo group. The proportion of patients with at least minimal improvement on the CGI-C was statistically significantly greater in the armodafinil group (69%) compared with the placebo group (53%, P = .012). Mean (SD) increase in Maintenance of Wakefulness Test sleep latency was numerically but not significantly greater following armodafinil (2.6 [7.1] min) versus placebo (1.1 [7.6] min, P = .30) treatment. Mean decrease in Epworth Sleepiness Scale score was greater in the armodafinil group (-6.3 [4.8]) than in the placebo group (-4.8 [4.9], nominal P = .003). Headache, dry mouth, and insomnia were the most common adverse events occurring with armodafinil treatment. There was no clinically significant effect on depression in either group as measured by the Quick Inventory of Depressive Symptomatology-Self-Report 16. CONCLUSIONS: Armodafinil significantly improved overall clinical condition related to excessive sleepiness as rated by the CGI-C and was well tolerated in patients with treated OSA and comorbid depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00518986.